State-dependent inhibition of cystic fibrosis transmembrane conductance regulator chloride channels by a novel peptide toxin

Matthew D. Fuller, Christopher H. Thompson, Zhi Ren Zhang, Cody S. Freeman, Eszter Schay, Gergely Szakács, Éva Bakos, Balázs Sarkadi, Denis McMaster, Robert J. French, Jan Pohl, Julia Kubanek, Nael A. McCarty

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Abstract

Peptide toxins from animal venom have been used for many years for the identification and study of cation-permeable ion channels. However, no peptide toxins have been identified that interact with known anion-selective channels, including cystic fibrosis transmembrane conductance regulator (CFTR), the protein defective in cystic fibrosis and a member of the ABC transporter superfamily. Here, we describe the identification and initial characterization of a novel 3.7-kDa peptide toxin, GaTx1, which is a potent and reversible inhibitor of CFTR, acting from the cytoplasmic side of the membrane. Thus, GaTx1 is the first peptide toxin identified that inhibits a chloride channel of known molecular identity. GaTx1 exhibited high specificity, showing no effect on a panel of nine transport proteins, including Cl+ and K- channels, and ABC transporters. GaTx1-mediated inhibition of CFTR channel activity is strongly state-dependent; both potency and efficacy are reduced under conditions of elevated [ATP], suggesting that GaTx1 may function as a non-competitive inhibitor of ATP-dependent channel gating. This tool will allow the application of new quantitative approaches to study CFTR structure and function, particularly with respect to the conformational changes that underlie transitions between open and closed states.

Original languageEnglish
Pages (from-to)37545-37555
Number of pages11
JournalJournal of Biological Chemistry
Volume282
Issue number52
DOIs
Publication statusPublished - Dec 28 2007

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Fuller, M. D., Thompson, C. H., Zhang, Z. R., Freeman, C. S., Schay, E., Szakács, G., Bakos, É., Sarkadi, B., McMaster, D., French, R. J., Pohl, J., Kubanek, J., & McCarty, N. A. (2007). State-dependent inhibition of cystic fibrosis transmembrane conductance regulator chloride channels by a novel peptide toxin. Journal of Biological Chemistry, 282(52), 37545-37555. https://doi.org/10.1074/jbc.M708079200